AN EXPLOSIVE OUTBREAK OF PRIMARY ATYPICAL PNEUMONIA IN A COLLEGE COMMUNITY' ROBERT A. SNYDER, M.D., HARRY B. HARDING, M.D., OPAL E. HEPLER, M.D. and LEONA B. YEAGER, M.D.2 N October, 1951, the Garrett Biblical be caused by Pasteurella tularensis. There I Institute of Northwestern University remained a larger group ,,·ith unproven at Evanston, Illinois, experienced an ex­ etiology, which has been labeled variously plosive outbreak of a severe respiratory "acute pneumonitis," "virus pneumonia," infection, with marked pulmonary infil­ "atypical bronchopneumonia," etc., but tration in almost every case. Through is more widely called "primary atypical the facilities of the virus laboratory of pneumonia. " North\\'estern University Medical School, Despite thorough investigations in a the pneumonitis was proven serologi­ number of excellent laboratorie, con­ cally to be primary atypical pneumonia. clusive evidence of the etiologic agent in It is our purpose, in this paper, to primary atypical pneumonia is still lack­ review briefly the history of primary ing. At least five seemingly different atypical pneumonia, to describe the clin­ infectious agents have been impEcated. ical features of the Garrett cases, to dis­ The experiments of Stokes et al. (4), cuss the laboratory differentiation of this Weir and Horsfall (5), Blake et al. (6), epidemic, and, finally, to summarize the and Eaton and cO\\'orkers (7) are "'ell information obtained from a standard documented and need not be revie\\"ed in epidemiological approach to this outbreak. detail. In 1946, the Commission on Acute Respiratory Diseases, working at Fort REVIEW OF LITERATURE Bragg, North Carolina (8), succeeded in Arrasmith (1 ), Bowen (2), and Allen transferring primary atypical pneumonia (3) were among the first to call attention to 16 out of 60 patients, using pooled to certain penumonias, occurring both specimens from typical cases. Twenty­ sporadically and in small epidemics, which six others developed an upper respiratory failed to conform to the accepted picture infection without pneumoni a. The of either lobar or bronchopneumonia. workers concluded that primary atypical Later, as the sulfonamides and penicillin pneumonia was caused or initiated by a became widely and effectively used against filter-passing agent, presumably a vim. the bacterial pneumonias, these so-called Though we still lack the abiEty to atypical pneumonias were further deline­ demonstrate the etiologic agent, there ated. In certain instances, the etiology remain two serologic tests, quite inde­ of these atypical pneumonias could be pendent of each other, which are useful clearly established as due to viruses or adjuncts to the diagnosis of primary rickettsiae such as those of psittacosis, atypical pneumonia. The one most .\\·idely influenza, Q fever, and lymphocytic chor­ used is the demonstration of cold ag­ iomeningitis. A few cases were found to glutinins (9, 10), these being present, de­ 'From the Student Health Service of Northwestern Uni· pending upon the severity of the case, versity; the Departments of l\1edicine. Bacteriology, and in 20 to 90 per cent (11) of the con­ Pathology of Northwestern University Medical School; and the Departments of Medicine and Pathology of valescent sera from these patients. Evanston Hospital. Received for puhlication, September 23, 1952. This test was highly useful in the Gar­ This investigation was supported in part by a research rett outbreak and \\·ill be discussed more grant from the National Institutes of Health, U. S. Public Health Service. fully later in this paper. The second 'The authors wish to gratefully acknowl edge the tech· nical assistance of Edna Murmann, M.s .. Nathalie Schmidt, serologic test is the demonstration of M.S., Jeanne Doucette, M.S., and Mary Robinson, B.S. agglutinins against a non-hemolytic strep- 327 328 QUA RTERLY BULLETIN, N.V. M.S. tococcu , de ignated Streprococcus MG. Mirick and Thomas (12), in 1945, iso­ TABLE I lated this microorganism from the lungs Frequency of Occurrence of Symptoms and of fatal cases of primary atypical pneu­ Signs in Nineteen Patients with a Clinical monia, and suggested it I\"aS implicated Diagnosis of Primary Atypical Pneumonia Fever . 19 in the cause of this disease. About 50 per Cough . .. ..... ... .. ... .. 19 cent of the cases of pri mary atypical Headache. 18 pneumonia develop these agglutinins. Myalgia... ... ..... .. ... 15 Ri,'ers (13) suggests three explanations Sore Throat . ....... .... , . 14 Chills . ... .. ... .... ...... 11 for th is phenomenon. Fir t, there may Sputum . .. .... 11 be a coincidental immunologic relation- Anorexia . ... .... .. .. ... 7 hip betll"een the bacterium and some Rhinit is.... .. .. 6 other infectious agent. Second, the reac­ Hoarseness .. 6 Photophobia. 4 tion may be caused by a secondary in­ Xausea . .. ..... .. 2 "asion of the microorganism. Third, the Insomnia . .... ~. 0 agglutination may result from a double Vomiting. ....... .. ... .. ... 0 infection ini tiated by the streptococcus Clinical Laboratory Findings and some other infectious agent, presum­ Leucocytosis. 1 ably a I·irus. Lymphocytosis (over 50% by diffe rential count) . 0 THE EPJDEMIC A'l' THE GARRE'!"!' X-ray pneu moni ti * . ... 14 BIBLICAL INSTl'ru,),E *T\\'o patient · exhibited rales \\'ithout The Garrett outbreak of primary sho\\'ing infi ltration on x-ray examination. atypieal pneumonia con isted of 19 cases, all of them clinically imilar and charac­ ing 3 to 4 lI"eeks after they became am­ teri ·tic of the generally accepted picture bulatory. of this disease. Fourteen of them lI'ere X-ray clearing u ually \\"a present developed lI'ithin a 4-day interval, be­ \\·ithin 5 to 10 days. Two cases, hOIl'ever, ginning October 14, follo ll'ed by 5 econd­ continued to have sli ght infiltration long ary cases ol'er a period of 5 days. T he after they lI'ere well. Five representative secondary Irave lasted hom October 20 x-rays are included (fi g, 1). th rOlwh October 24. T he frequency of Due to the small number of cases, no . igns and symptoms is listed in Ta,b[e 1. conclusions \I'ere reached as to the effi­ All illnesses began lI'ith a rapidly develop­ cacy of treatment. T he duration of illness ing upper respiratory infection, accom­ \\'as remarkably similar lI'hether aureo­ panied by a 101l"-grade fever, headache, mycin, chloromycetin, terramycin , or no malai,'e, and generalized aching. Within treatment I\'as used. Three persons wi th 2 to 3 days mriously productive cough severe bilateral involvement lI'ere ill del'eloped, Irhile the fever ranged up to longer than the others and did not seem 103 F. As is usual in this disea,'e, phys­ to reo pond to any of t he antibiotics, ical findings in the che t lI'ere at I"ari ance T hus Ire did not confirm the general im­ lI"ith the x-ray findings. Of 14 persons pre sion one deri ves from reading the Irith marked x-ray find ings, 5 presented literatUl'e, namely, that aureomycin is an only slight physical find ings of pneu­ effective drug in primary atypical pneu­ monitis, lI·hereas examination of 2 other monia (14), patients in the epidemic revealed defin ite phy ical finding of pneumonia Iri th ab­ LABORATORY STUDIES 'ent or slight x-ray el" idence. Both of At the time the outbreak began, the the, 'e latter indil'iduals developed cold nature of the causal agent was, of course, agglutinins lI·ith titers of diagnostic sig­ unkno\\·n. The cl ini cal picture and the nificance. The duration of illness was 10 x-ray findings of the first 15 cases, ho\\'­ days on the average. Temperature con­ eyer, strongly indicated the probable tinued, u 'ually 101l'-grade, but in 3 in­ diagnosis of primary atypical pneumonia. stance. was high (103 to 104 F.) during Therefore microbiological laboratory in­ the height of the pneumonitis. Almost vestigation Irere conducted as follows: all patients noted persistent fatigue, last- 1. Bacteri ological examination of spu- SNYDER ET AL.- PRIMARY ATYPICAL PNEUMONIA 329 Fig. 1. Typical x-my films jTOm patients in Gar1'elt epidemic. A , Patient, C. K. Film taken October 14, 1951. Note injiltmtion in right lower lobe w'ea and increased hilar markings. B, Patient J. J . Film taken October 22, 1951 . There is a circulw' a1'ea of increased density in region of fifth and sixth 1'ib (on left). C, Patient J. S. Film taken October 22, 19.51 . Note clouding and increased density in left costophrenic angle. Note also the increased hilar mw·kings. D, Patient M. J . Film taken October 29, 1951. The moltled lesion in right hmg W'W is quite prominent. E, Patient J. M u. Lesions may be seen in both lung bases . tum samples in the acute phase of each stained by Gram's method. Portions of patie~t 's illness for predominating micro­ each specimen \rere then inoculated onto orgamsms. Loeffler's serum medium, eosin methylene 2. A survey for virus complement-fix­ blue agar, chocolate agar, rabbit blood ing antibodies in the acute and conval­ agar, and thioglycollate medium. Growth escent phases of each patient's illness. appearing on these media \ras identified 3. A determination of cold-agglutinin by appropriate methods (15). Table II titers in the acute and convalescent phases summarizes the species of organisms of each patient's illness. found in this investigation together ,,·i th their frequency of occurrence on the Bacteriological Examinations: above media. Since in no instance "'as a predominating pathogen found, these Sputum specimens4 obtained in the acute phase from 11 of the patients in­ results would indicate that the organisms volved in the epidemic were examined for isolated from these patients lacked eti­ the presence of predominating micro­ ologic significance. organi!';ms. Direct films were made and Complement Fixation Studies : 4Twelve specimens of sputum , including the above 11, were examined October 25, 1951 b.l'chick-embr.l'o inocu­ Using 14 different viral and rickettsial lation for the presence of virus by Mr.